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WO2018172821A1 - Nouveaux sels d'addition de tofacitinib et leur procédé de préparation - Google Patents

Nouveaux sels d'addition de tofacitinib et leur procédé de préparation Download PDF

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Publication number
WO2018172821A1
WO2018172821A1 PCT/IB2017/051689 IB2017051689W WO2018172821A1 WO 2018172821 A1 WO2018172821 A1 WO 2018172821A1 IB 2017051689 W IB2017051689 W IB 2017051689W WO 2018172821 A1 WO2018172821 A1 WO 2018172821A1
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acid
tofacitinib
salt
addition salts
solvates
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Sri Ramakrishna AVIRNENI
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Phalanx Labs Private Ltd
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Phalanx Labs Private Ltd
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Priority to KR1020197030717A priority Critical patent/KR20190130609A/ko
Priority to PCT/IB2017/051689 priority patent/WO2018172821A1/fr
Publication of WO2018172821A1 publication Critical patent/WO2018172821A1/fr
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    • A—HUMAN NECESSITIES
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
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    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/24—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having more than one carboxyl group bound to the carbon skeleton, e.g. aspartic acid
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    • C07C57/03—Monocarboxylic acids
    • C07C57/10—Sorbic acid
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/01—Saturated compounds having only one carboxyl group and containing hydroxy or O-metal groups
    • C07C59/06—Glycolic acid
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/235—Saturated compounds containing more than one carboxyl group
    • C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
    • C07C59/255—Tartaric acid
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    • C07C62/04—Saturated compounds containing hydroxy or O-metal groups with a six-membered ring
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    • C07C62/18—Saturated compounds containing keto groups
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    • C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
    • C07C65/03—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups monocyclic and having all hydroxy or O-metal groups bound to the ring
    • C07C65/05—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups monocyclic and having all hydroxy or O-metal groups bound to the ring o-Hydroxy carboxylic acids
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    • C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
    • C07C65/19—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups having unsaturation outside the aromatic ring
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/21—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups
    • C07C65/28—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups having unsaturation outside the aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
    • C07C69/12—Acetic acid esters
    • C07C69/14—Acetic acid esters of monohydroxylic compounds
    • C07C69/145—Acetic acid esters of monohydroxylic compounds of unsaturated alcohols
    • C07C69/157—Acetic acid esters of monohydroxylic compounds of unsaturated alcohols containing six-membered aromatic rings
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
    • C07C69/732—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids of unsaturated hydroxy carboxylic acids
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
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    • C07C2601/14—The ring being saturated
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    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/40—Ortho- or ortho- and peri-condensed systems containing four condensed rings

Definitions

  • the present invention relates to process for the preparation of Tofacitinib, novel Tofacitinib addition salts.
  • Tofacitinib (3R,4R)-4-methyl-3-(methyl-7H-pyrrolo [2,3-d]pyrimidin-4-ylamino-P-oxo-l- piperidine propanenitrile (Formula-I) generally named as Tofacitinib, (formerely Tasocitinib CP- 690550), has the following chemical structure:
  • Tofacitinib as well as certain pharmaceutically acceptable salts thereof, is described in WO2001/042246, WO2002/096909, WO2003/048162, WO2012/135338, WO2013/090490 and US2015/0225406 describes crystalline forms and describes process for preparing certain other Tofacitinib salts.
  • WO 2012/137111 discloses novel crystalline and non-crystalline forms of (3R,4R)-4-methyl-3- (methyl-7H-pyrrolo [2,3-d]pyrimidin-4-ylamino-P-oxo-l -piperidine propanenitrile, pharmaceutical composition containing the same, preparations thereof and the uses thereof.
  • US 2015/0225406 Al discloses solid and crystalline forms of Tofacitinib hydrochloride and Tofacitinib hydrobromide, processes for the preparation thereof and processes for the use thereof in preparing Tofacitinib citrate are provided.
  • Yet another object of present invention provides a novel acid addition salts, those can improve the taste of the Tofacitinib as Tofacitinib citrate is highly bitter in taste.
  • Yet another object of the present invention is to provide process for preparing novel acid addition salts of Tofacitinib.
  • Yet another object of the present invention is to provide a pharmaceutical composition comprising acid addition salts of Tofacitinib. Summary of the invention:
  • the improved pharmaceutical property is selected from the group consisting of: increased solubility, increased dissolution, increased bioavailability, increased dose response, decreased form diversity, more desired morphology, more desired taste, or other property described herein.
  • the present invention provides novel acid addition salts of Tofacitinib of Formula-I its solid state forms or its solvates or hydrates thereof;
  • the acid addition salts are selected from the group comprising an anti- oxidative acids such as Gentisic acid, p-coumaric acid, ferulic acid, sinapic acid, caffeic acid, chlorogenic acid, caftaric acid, coutaric acid, pantothenic acid, Erythorbic acid and the like; and other acids for better taste are such as Cyclamic acid, Saccharin and the like, and the other salts like asparatic acid, sorbic acid, Cholic acid, Poly glutamic acid, pimelic acid, L-Pyroglutamic acid, Glucoheptonoic acid, Glycolic acid, acetylsalicylic acid, meso-tartaric acid, Glyoxylic acid, Pyruvic acid, lipoic acid, quinic acid, meso-tartaric acid and Pantothenic acid.
  • an anti- oxidative acids such as Gentisic acid, p-coumaric acid, ferulic acid, sinapic acid, caffeic acid,
  • the present invention provides a process for preparation of acid addition salts of Tofacitinib of Formula-I or its solvates or hydrates thereof, comprising:
  • the acid addition salts are selected from the group comprising anti-oxidative acids such as Gentisic acid, p-coumaric acid, ferulic acid, sinapic acid, caffeic acid, chlorogenic acid, caftaric acid, coutaric acid, pantothenic acid, Erythorbic acid and the like; and other acids for better taste are selected from the group comprising Cyclamic acid, Saccharin and the like, and the other acids like asparatic acid, sorbic acid, Cholic acid, Poly glutamic acid, pimelic acid, L- Pyroglutamic acid, Glucoheptonoic acid, Glycolic acid, acetylsalicylic acid, meso-tartaric acid, Glyoxylic acid, Pyruvic acid, lipoic acid, quinic acid, meso-tartaric acid and Pantothenic acid.
  • anti-oxidative acids such as Gentisic acid, p-coumaric acid, ferulic acid, sinapic acid, caffeic acid, chlorogenic
  • the present invention provides crystalline form of Tofacitnib compound of Formula-I.
  • Figure- 1 is the characteristic powder X-ray diffraction (XRD) pattern of Tofacitinib base.
  • Figure-2 is the characteristic powder X-ray diffraction (XRD) pattern of Tofacitinib aspartate salt.
  • the present invention addresses a need in the art by providing new acid addition salts of Tofacitinib, or its solvates or hydrates thereof.
  • the present invention provides novel acid addition salts of Tofacitinib of Formula-I or its solid state forms or solvates or hydrates thereof;
  • the acid addition salts are selected from the group comprising an anti- oxidative acids such as Gentisic acid, p-coumaric acid, ferulic acid, sinapic acid, caffeic acid, chlorogenic acid, caftaric acid, coutaric acid, pantothenic acid, Erythorbic acid and the like; and other acids for better taste are such as Cyclamic acid, Saccharin and the like, and the other salts like asparatic acid, sorbic acid, Cholic acid, Poly glutamic acid, pimelic acid, L-Pyroglutamic acid, Glucoheptonoic acid, Glycolic acid, acetylsalicylic acid, meso-tartaric acid, Glyoxylic acid, Pyruvic acid, lipoic acid, quinic acid, meso-tartaric acid and Pantothenic acid.
  • an anti- oxidative acids such as Gentisic acid, p-coumaric acid, ferulic acid, sinapic acid, caffeic acid,
  • the present invention provides crystalline Tofacitinib salt characterized by an X-Ray diffraction (XRD) pattern substantially in accordance with Figures.
  • XRD X-Ray diffraction
  • the present invention provides a process for preparation of acid addition salts of Tofacitinib of Formula-I or its solvates or hydrates thereof, comprising:
  • the acid addition salts are selected from the group comprising anti-oxidative acids such as Gentisic acid, p-coumaric acid, ferulic acid, sinapic acid, caffeic acid, chlorogenic acid, caftaric acid, coutaric acid, pantothenic acid, Erythorbic acid and the like; and other acids for better taste are such as Cyclamic acid, Saccharin and the like, and the other salts like asparatic acid, sorbic acid, Cholic acid, Poly glutamic acid, pimelic acid, L-Pyroglutamic acid, Glucoheptonoic acid, Glycolic acid, acetylsalicylic acid, meso-tartaric acid, Glyoxylic acid, Pyruvic acid, lipoic acid, quinic acid, meso-tartaric acid and Pantothenic acid.
  • anti-oxidative acids such as Gentisic acid, p-coumaric acid, ferulic acid, sinapic acid, caffeic acid, chlorogenic acid,
  • the Tofacitinib in the step a) may be any crystalline or other form of Tofacitinib, including various solvates, hydrates or Tofacitinib obtaining as existing solution from a previous processing step.
  • the one or more solvent include, but are not limited to water, lower alcohols, ketones, esters, ethers, C5-C7 linear, branched or cyclic, saturated or unsaturated hydrocarbons, nitriles, halogenated hydrocarbons, or mixtures thereof.
  • the suitable organic solvent includes, but are not limited to methanol, ethanol, isopropanol, acetone, methylethylketone, methyl iso butyl ketone, methyl acetate, ethyl acetate, isopropyl acetate, tetrahydrofuran (THF), isopropyl ether (IPE), ter-butyl methyl ether, acetonitrile, propionitrile, methylene chloride, chloroform, toluene, cyclohexane, hexane, heptanes and the like and the mixtures thereof.
  • the solution comprising Tofacitinib free base and acid of step a) can be provided by mixing the solution of Tofacitinib free base with acid.
  • solution of Tofacitinib free base intern can be provided by dissolving Tofacitinib free base in suitable solvent.
  • solution of acid may be added to the solution of Tofacitinib either in natural state or in solution.
  • solution of acid can be prepared by dissolving the acid in a suitable solvent.
  • the temperature suitable for providing a solution comprising Tofacitinib and acid in one or more solvents is from ambient temperature to about boiling point of the solvent; preferably at a temperature of about 30°C to about 100°C.
  • the isolation of the Tofacitinib acid addition salt can be induced by reducing the temperature of reaction mixture, especially if initial temperature of reaction mixture is elevated.
  • the isolation can also be induced by reduction of solution volume, preferably under reduced pressure, spray drying, freeze drying, agitated thin film evaporator (ATFE), by complete evaporation of solvent or crystallization.
  • the isolation may be caused by adding an anti-solvent to the reaction solution to precipitation.
  • the isolated acid addition salt of Tofacitinib can optionally be washed with one or more organic solvents, and finally resulted pure acid addition salt of Tofacitinib may be recovered by any conventional methods or known techniques.
  • the suitable solvent used include any suitable solvent as described herein; preferably the suitable solvent is selected from the group consisting of water, methanol, ethanol, acetone, THF, Acetonitrile, ethyl acetate, IPE and mixtures thereof.
  • the resulted pure acid addition salt of Tofacitinib may be recovered by any conventional methods such as filtration, solvent precipitation, spray drying, freeze drying, agitated thin film evaporator (ATFE) and the like.
  • ATFE agitated thin film evaporator
  • the present invention provides an improved process for the preparation of 3-((3R,4R)-4-methyl- 3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidine-l-yl)-3-oxopropionitrile compound of formula-I, which comprising of:
  • Tofacitinib base prepared according to such procedure exhibits a powder X-ray diffraction pattern substantially in accordance with Figure. 1.
  • the present invention provides a process for preparing acid addition salt of Tofacitinib, wherein the acid addition salt, comprising
  • the suitable solvent used is selected from the group consisting of water, methanol, ethanol, acetone, THF, acetonitrile, ethyl acetate, IPE and mixtures thereof, preferably water.
  • the solution may be formed by heating the mixture at a temperature of about 25-100°C, preferably about 85°C to about 100°C.
  • the acid addition salt can be isolated by any known techniques such as cooling the solution to precipitation, crystallization, solvent precipitation, spray drying, freeze drying, agitated thin film evaporator (ATFE) and the like.
  • Tofacitinib Aspartic acid salt prepared according to such procedure exhibits a powder X-ray diffraction pattern substantially in accordance with Figure. 2.
  • Tofacitinib Aspartic acid salt prepared according to such procedure exhibits a differential scanning calorimetric (DSC) thermogram substantially in accordance with Figure-3.
  • the present invention provides a process for preparing acid addition salts of Tofacitinib, wherein the acid addition salt, comprising
  • the suitable solvent used is selected from the group consisting of water, methanol, ethanol, acetone, THF, acetonitrile, ethyl acetate, IPE and mixtures thereof.
  • the addition salt may be formed by heating the mixture at a temperature of about 20°C to about reflux temperature, preferably about 40°C to about 100°C.
  • the acid addition salt can be isolated by any known techniques such as cooling the solution to precipitation, crystallization, solvent precipitation, spray drying, freeze drying, agitated thin film evaporator (ATFE) and the like.
  • the present invention provides a process for preparing acid addition salts of Tofacitinib, wherein the acid addition salt, comprising
  • the suitable solvent used is selected from the group consisting of water, methanol, ethanol, acetone, THF, acetonitrile, ethyl acetate, IPE and mixtures thereof.
  • the solution may be formed by heating the mixture at a temperature of about 30°C to about reflux temperature, preferably about 40°C to about 100°C.
  • the acid addition salt can be isolated by any known techniques such as cooling the solution to precipitation, crystallization, solvent precipitation, spray drying, freeze drying, agitated thin film evaporator (ATFE) and the like.
  • the present invention provides a process for preparing acid addition salts of Tofacitinib, wherein the acid addition salt, comprising
  • the suitable solvent used is selected from the group consisting of water, methanol, ethanol, acetone, THF, acetonitrile, ethyl acetate, IPE and mixtures thereof.
  • the solution may be formed by heating the mixture at a temperature of about 30°C to about reflux temperature, preferably about 40°C to about 100°C.
  • the acid addition salt can be isolated by any known techniques such as cooling the solution to precipitation, crystallization, solvent precipitation, spray drying, freeze drying, agitated thin film evaporator (ATFE) and the like.
  • the present invention provides a process for preparing acid addition salts of Tofacitinib, wherein the acid addition salt, comprising
  • the suitable solvent used is selected from the group consisting of water, methanol, ethanol, acetone, THF, acetonitrile, ethyl acetate, IPE and mixtures thereof.
  • the solution may be formed by heating the mixture at a temperature of about 30°C to about reflux temperature, preferably about 40°C to about 100°C.
  • the acid addition salt can be isolated by any known techniques such as cooling the solution to precipitation, crystallization, solvent precipitation, spray drying, freeze drying, agitated thin film evaporator (ATFE) and the like.
  • the present invention provides a process for preparing acid addition salts of Tofacitinib, wherein the acid addition salt, comprising
  • the suitable solvent used is selected from the group consisting of water, methanol, ethanol, acetone, THF, acetonitrile, ethyl acetate, IPE and mixtures thereof.
  • the solution may be formed by heating the mixture at a temperature of about 30°C to about reflux temperature, preferably about 40°C to about 100°C.
  • the acid addition salt can be isolated by any known techniques such as cooling the solution to precipitation, crystallization, solvent precipitation, spray drying, freeze drying, agitated thin film evaporator (ATFE) and the like.
  • the present invention provides a process for preparing acid addition salts of Tofacitinib, wherein the acid addition salt, comprising
  • the suitable solvent used is selected from the group consisting of water, methanol, ethanol, acetone, THF, acetonitrile, ethyl acetate, IPE and mixtures thereof, preferably acetone.
  • the solution may be formed by heating the mixture at a temperature of about 30°C to about reflux temperature, preferably about 40°C to about 100°C.
  • the acid addition salt can be isolated by any known techniques such as cooling the solution to precipitation, crystallization, solvent precipitation, spray drying, freeze drying, agitated thin film evaporator (ATFE) and the like.
  • the present invention provides crystalline form of Tofacitinib base and novel acid addition salts of Tofacitinib, having a chemical purity of 96% or more as measured by HPLC, preferably 99% or more, more preferably 99.5% or more.
  • the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of acid addition salts of Tofacitinib of the present invention with at least one pharmaceutically acceptable carrier or other excipients.
  • the pharmaceutical composition can be useful for rheumatoid arthritis (RA) and is being studied for treatment of psoriasis, inflammatory bowel disease, and other immunological diseases, as well as for the prevention of organ transplant rejection, xeno transplantation, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, Type I diabetes and complications from diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, Alzheimer's disease, leukemia and other indications, where immunosuppression would be desirable.
  • RA rheumatoid arthritis
  • Tofacitinib free base obtained from the above said example dissolved in water and 2.39 gm of gentisic acid was stirred at ambient temperature. Distilled off solvent completely to obtain Tofacitinib gentisic acid salt.
  • Tofacitinib free base obtained from the above said example dissolved in water and 1.47 gm of glyoxylic acid was stirred at ambient temperature. Filtered the mass and dried to obtain Tofacitinib glyoxylic acid salt.

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Abstract

La présente invention concerne plusieurs nouveaux sels d'addition de tofacitinib et leurs formes solides, hydrates, solvates ainsi que leurs utilisations en tant que médicaments.
PCT/IB2017/051689 2017-03-23 2017-03-23 Nouveaux sels d'addition de tofacitinib et leur procédé de préparation Ceased WO2018172821A1 (fr)

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PCT/IB2017/051689 WO2018172821A1 (fr) 2017-03-23 2017-03-23 Nouveaux sels d'addition de tofacitinib et leur procédé de préparation

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CN109879879A (zh) * 2019-03-25 2019-06-14 国药集团容生制药有限公司 一种托法替布中间体的制备工艺
WO2019182322A1 (fr) * 2018-03-20 2019-09-26 삼진제약주식회사 Nouveau sel, son procédé de préparation et composition pharmaceutique le comprenant
CN110724146A (zh) * 2019-11-04 2020-01-24 四川大学 一种枸橼酸托法替布的制备方法
WO2020183295A1 (fr) 2019-03-13 2020-09-17 Intas Pharmaceuticals Ltd. Procédé de préparation de tofacitinib et son sel pharmaceutiquement acceptable
CN115236261A (zh) * 2022-05-10 2022-10-25 汉瑞药业(荆门)有限公司 一种托法替尼中间体纯度的hplc-uv检测方法

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WO2013090490A1 (fr) * 2011-12-15 2013-06-20 Ratiopharm Gmbh Sels de tofacitinib
US20160122354A1 (en) * 2013-06-05 2016-05-05 Srinivasan Thirumalai Rajan PROCESS FOR THE PREPARATION OF (3R,4R)-4-METHYL-3-(METHYL-7H-PYRROLO[2,3-D]PYRIMIDIN-4-YL-AMINO)-ß-OXO-1-PIPERIDINEPROPANENITRILE AND ITS SALTS
US20160346200A1 (en) * 2014-02-07 2016-12-01 Auspex Pharmaceuticals, Inc. Novel pharmaceutical formulations

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US20030130292A1 (en) * 2001-12-06 2003-07-10 Pfizer Inc. Novel crystalline compound
WO2013090490A1 (fr) * 2011-12-15 2013-06-20 Ratiopharm Gmbh Sels de tofacitinib
US20160122354A1 (en) * 2013-06-05 2016-05-05 Srinivasan Thirumalai Rajan PROCESS FOR THE PREPARATION OF (3R,4R)-4-METHYL-3-(METHYL-7H-PYRROLO[2,3-D]PYRIMIDIN-4-YL-AMINO)-ß-OXO-1-PIPERIDINEPROPANENITRILE AND ITS SALTS
US20160346200A1 (en) * 2014-02-07 2016-12-01 Auspex Pharmaceuticals, Inc. Novel pharmaceutical formulations

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019182322A1 (fr) * 2018-03-20 2019-09-26 삼진제약주식회사 Nouveau sel, son procédé de préparation et composition pharmaceutique le comprenant
WO2020183295A1 (fr) 2019-03-13 2020-09-17 Intas Pharmaceuticals Ltd. Procédé de préparation de tofacitinib et son sel pharmaceutiquement acceptable
EP3938370A4 (fr) * 2019-03-13 2022-12-21 Intas Pharmaceuticals Ltd. Procédé de préparation de tofacitinib et son sel pharmaceutiquement acceptable
US12269830B2 (en) 2019-03-13 2025-04-08 Intas Pharmaceuticals Ltd. Process for preparation of tofacitinib and pharmaceutically acceptable salt thereof
CN109879879A (zh) * 2019-03-25 2019-06-14 国药集团容生制药有限公司 一种托法替布中间体的制备工艺
CN110724146A (zh) * 2019-11-04 2020-01-24 四川大学 一种枸橼酸托法替布的制备方法
CN110724146B (zh) * 2019-11-04 2022-03-11 四川大学 一种枸橼酸托法替布的制备方法
CN115236261A (zh) * 2022-05-10 2022-10-25 汉瑞药业(荆门)有限公司 一种托法替尼中间体纯度的hplc-uv检测方法
CN115236261B (zh) * 2022-05-10 2024-04-19 武汉海特生物创新医药研究有限公司 一种托法替尼中间体纯度的hplc-uv检测方法

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